Galactose is an abundant hexose existing as lactose in milk, dairy products, fruits, vegetables and many other foods (Acosta, P. B. and K. C. Gross, Eur. J. Pediatr, 1995. 154(7 Suppl. 2): p. S87-92; Berry, G. T., et al., J. Inherit. Metab. Dis, 1993. 16(1): p. 91-100). It is metabolized through an evolutionarily conserved pathway referred to as the Leloir pathway (Leloir, L. F., Arch Biochem, 1951. 33(2): p. 186-90). The first enzyme of the pathway, galactokinase (GALK), converts α-D-galactose to galactose-1-phosphate (gal-1-p) (Atkinson, M. R., E. Johnson, and R. K. Morton, Nature, 1959. 184: p. 1925-7). Then, in the presence of the second enzyme, galactose-1-phosphate uridyltransferase (GALT), gal-1-P will react with UDP-glucose to form UDP-galactose and glucose-1-phosphate (Arabshahi, A., et al., Biochemistry, 1986. 25(19): p. 5583-9).
Deficiency of GALT results in a potentially lethal disorder called Classic Galactosemia (CG) (Isselbacher, K. J., et al., Science, 1956. 123(3198): p. 635-6; Rennert, O. M., Annals of clinical and laboratory science, 1977. 7(6): p. 443-8). Patients with CG accumulate high level of gal-1-p which can result in severe disease during the newborn period, including liver failure, coagulopathy, coma, and death if not treated (Goppert, F., Klin. Wschr., 1917(54): p. 473-477; Mason H, T. M., Am. J. Dis. Child., 1935(50): p. 359-374; Tyfield, L., et al., Hum. Mutat., 1999. 13(6): p. 417-30). Although removal of galactose from the diet can prevent neonatal death, CG patients still develop chronic complications such as premature ovarian insufficiency (POI), ataxia, speech dyspraxia and mental retardation even in galactose-restricted diet (Waggoner, D., Buist, N R M, Donnell, G N, Journal of Inherited Metabolic Disorders, 1990. 13: p. 802-818; Waggoner, D., Buist, N R M, International Pediatrics, 1993. 8: p. 97-100).
The mechanisms for the above chronic complications remain uncertain, but several lines of evidences indicate accumulation of gal-1-p is a major factor that contributes to these complications. Except for cataracts, patients with an inherited deficiency of GALK do not experience the complications observed in GALT-deficient patients (Gitzelmann, R., H. J. Wells, and S. Segal, Eur. J. Clin. Invest., 1974. 4(2): p. 79-84; Gitzelmann, R., J. Pediatr., 1975. 87(6 Pt 1): p. 1007-8). Similarly, while gal7 (i.e., GALT-deficient) mutant yeast stops growing upon galactose challenge, a gal 7 gal1 double mutant strain (i.e., GALT- and GALK-deficient) is no longer sensitive to galactose (Douglas, H. C. and D. C. Hawthorne, Genetics, 1964. 49: p. 837-44; Douglas, H. C. and D. C. Hawthorne, Genetics, 1966. 54(3): p. 911-6). A significant amount of galactose is found in non-dairy foods such as vegetables and fruits, and more importantly, galactose is also produced endogenously from the natural turnover of glycolipids and glycoproteins. Moreover, using isotope labeling, Berry et al. demonstrated that a 50 kg adult male could produce up to 2 grams of galactose per day (Berry, G. T., et al., Mol. Genet. Metab., 2004. 81(1): p. 22-30; Berry, G. T., et al., Eur. J. Pediatr., 1997. 156 Suppl. 1: p. S43-9; Berry, G. T., et al., Lancet, 1995. 346(8982): p. 1073-4).
In addition, it is known that GALKmodifies the PTEN/AKT pathway in a number of human tissues and human cell lines. The galactose-1-phosphate produced by GALK feeds into glycolysis. GALK1 is over-expressed in a number of tumors. Thus, inhibition of GALK may down regulate the PTEN/ATK pathway and therefore interfere with tumor growth and/or development.
The foregoing shows that there is an unmet need for inhibitors of galactokinase enzyme and agents for the prophylaxis and/or therapy of diseases preventable or treatable by inhibiting the enzyme.